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462 Chapter 18 Schizophrenia
Corticolimbic
Front
of head
regions
3
1
Striatum
(caudate
putamen)
Substantia
nigra
Back
of head
Arcuate nucleus
of hypothalamus
Median eminence
of hypothalamus
Figure 18.3 Three dopamine neuronal systems in the brain.
(1) The nigrostriatal system involved in movement planning (affected in Parkinson’s
disease); (2) the hypothalamic system involved in endocrine control; (3) the ventral
tegmental–corticolimbic system which is implicated in schizophrenia.
2
e dopamine cell bodies form clusters that send
projections to major areas of the brain where neuronal
function is inuenced by the dopamine released from
their nerve terminals. e three main systems are
illustrated in Figure 18.3.
• e cell bodies densely packed into the substantia nigra
send axons to terminate in the basal ganglia (striatum,
caudate/putamen, globus pallidus). is pathway is
essential for movement control; as discussed in
Chapter 17, its degeneration is the central pathology in
Parkinson’s disease. Its disruption by antipsychotic
drugs results in the movement disorder side eects (i.e.
extrapyramidal side eects) discussed below and
illustrated in Workbook 15.
• e shortest pathway is the population of dopamine-
releasing neurons in the hypothalamus. e dopamine
released here inhibits prolactin release from the
pituitary into the bloodstream. is explains a further
unwanted eect of dopamine antagonist (antipsychotic
drug) therapy, elevated blood prolactin
(hyperprolactinaemia), which can result in conditions
such as male breast enlargement (gynaecomastia).
• e longest pathway is from clusters of cell bodies in
the ventral tegmental system not far from the
substantia nigra. is pathway sends axons all the way
up to the cortex and limbic systems, including the
Ventral tegmental
nuclei
frontal lobes, nucleus accumbens, amygdala, and
hippocampus. ese areas are involved in higher
mental functions, emotional responses, memory,
selective attention, and appropriate response to
positive and negative events. It is not surprising,
therefore, that of the three dopamine systems, this is
the one that has been associated with schizophrenia
and the therapeutic response to antipsychotic
medication.
In Box 18.1 the ve main dopamine receptor subtypes
(D1–D5) are described. It has been shown that while D1
and D2 are widespread throughout the brain, the
relatively selective localization of D3 and D4 receptors in
the corticolimbic projection areas is of particular
interest. e relative paucity of these subtypes in the
caudate/putamen makes them interesting in
antipsychotic drug development, and provides the
possibility of a drug that acts with partial selectivity in
the corticolimbic areas. ere has been a focus of
attention on D4 receptors because of the clinical value of
clozapine (see below), an eective antipsychotic with
relative selectivity for D4 receptors. More recently, there
has been interest in D3 receptor antagonists as eective
antipsychotic agents which could treat cognitive and
negative symptoms of schizophrenia without unwanted
movement eects.
Box 18.2
Dopamine, glutamate, and the biological basis of schizophrenia
e biology of schizophrenia has been the subject of
intense research over the years. Fascinating advances
have been made from both molecular and
developmental approaches. at this has not resulted
in a unied comprehensible theory that stands the test
of time and directs clinical practice is not surprising
given that we have only a very crude understanding of
the way the brain works in terms of higher mental
functions. Given the diversity of the pathology across
individual patients it is quite possible that such a
unied theory will never be forthcoming. Here we
shall only introduce two of the mainstream concepts:
• the dopamine hypothesis, which has proved the
most durable and the most inuential in terms of
understanding drug therapy
• the glutamate hypothesis, which is relatively new
and is proposed as the most promising route for
entirely novel antipsychotic drugs.
The dopamine hypothesis
At its simplest the dopamine hypothesis states:
Schizophrenia is a result of an overactive dopamine
system in the corticolimbic regions of the brain.
ere are many variations on this simple expression of
the theory, but they all include an element of
dopamine overactivity in part of the brain or at certain
dopamine receptor subtypes (see Box 18.1).
Some of the evidence for the dopamine hypothesis
that has stood the test of time is as follows.
1. All antipsychotic drugs are dopamine antagonists.
(But while dopamine antagonism is very rapid, the
clinical antipsychotic eect is delayed; this
weakens the support for a simple dopamine
overactivity hypothesis.)
2. Amphetamine, which increases dopamine
availability in the synapse, may produce a
psychosis-like state. (is is not as good a mimic of
a schizophrenic psychotic episode as is seen with
phencyclidine (see below).)
3. Hallucinations can be a side eect of -dopa
therapy for Parkinson’s disease (see Chapter 17,
Section 17.3.4).
4. In some, but not all, studies D2 receptor density
was greater in post-mortem schizophrenic brains
than in matched controls. However, not all of these
ndings have proved reproducible.
5. Imaging studies in live patients (e.g. by positron
emission tomography):
a) dopamine receptor occupancy by endogenous
dopamine is greater in schizophrenic patients
b) the synaptic level of dopamine is higher in
schizophrenic patients
c) amphetamine gives a higher release of
dopamine in schizophrenic patients (i.e. more
dopamine is available for release in the
dopaminergic terminals of schizophrenic
patients than in matched controls).
While the evidence base for dopamine dysregulation
being the cause of schizophrenia may seem modest, it
has retained a dominant position over many years,
perhaps in part because it sits alongside the
dopaminergic theory for the action of antipsychotic
drugs.
The dopamine hypothesis refined: overactivity at
D2 receptors (corticolimbic) and underactivity at
D1 receptors (prefrontal cortex)
Many renements of the dopamine hypothesis have
been proposed. An inuential example is the
hypothesis of opposite inuences of D1 and D2
receptors. It is clear that negative symptoms are
resistant to D2 antagonism, and that activation of D1
receptors in the frontal cortex is required for normal
function. is leads to the suggestion that overactive
D2 receptors (corticolimbic areas) cause positive
symptoms, and a decit in dopamine stimulation of D
receptors (prefrontal cortex) contributes to negative
and cognitive symptoms.
The glutamate hypothesis
More recently the glutamate hypothesis has focused
on the role of the NMDA glutamate receptor.
Glutamate is the major excitatory neurotransmitter in
the brain (see Chapter 16, Box 16.1). It is activation of
glutamate receptors, found on essentially all brain
1
Box 18.2 Dopamine, glutamate, and the biological basis of schizophrenia
Glycine
Glutamate
Glutamate
neurons, that provides the driving force for neuronal
activity in the brain. It is this system that we have
encountered when considering the action of certain
antiepileptic drugs in Chapter 16.
Glutamate receptors include a class called NMDA
receptors. ese are ion channel receptors, i.e. they
cross the cell membrane (Chapter 16, Box 16.1, Figure
b) and contain an intrinsic ion channel for calcium
and sodium ions. When activated, the channel opens
and these ions enter the cell along concentration
gradients and lead to depolarization of the cell.
Activation of NMDA receptors therefore has an
excitatory eect.
A glutamate hypothesis was rst suggested following a
report in 1980 of reduced glutamate levels in the
cerebrospinal uid of schizophrenia patients. Despite
the fact that there has been diculty in replicating this
nding, a glutamate hypothesis has gained ground,
supported by other evidence presented below. e
glutamate hypothesis at its simplest is: Schizophrenia
is a result of underactivity at the NMDA glutamate
receptors in the brain.
Some of the evidence for this hypothesis is listed
below. (It should be noted that not all these ndings
have been replicated in every study.)
1. e drug of abuse, phencyclidine (PCP; ‘angel
dust’), can induce a psychosis-like state that is a
good mimic of acute schizophrenic psychosis. PCP
is an antagonist at NMDA receptors. Other NMDA
antagonists (e.g. ketamine and dizocilpine) can
also give rise to psychosis-like symptoms.
2. Neuropathological evidence:
a) reduced gene expression of messenger RNA for
NMDA receptors
b) reduced glutamate in cerebrospinal uid
c) reduced glutamate uptake sites (a pre-synaptic
marker for glutaminergic terminals) on autopsy
(post-mortem tissue).
3. Drugs enhancing NMDA function (e.g. glycine; see
below) may reduce negative symptoms.
is last point implies a route for novel antipsychotic
drug development. In addition to glutamate acting at
its binding site, a requirement for NMDA receptor
activation is that glycine occupies its own separate
binding site on the NMDA receptor complex (see
Figure a). Glycine therefore acts as an excitatory
co-transmitter in the brain.
Activation of glutamate receptors by a glutamatemimetic drug would have widespread undesirable
eects in the brain. However, enhancing NMDA
receptor activity by increasing glycine binding has
been considered a possible therapeutic approach,
giving rise to two strategies for drug development.
1. Administration of glycine agonists. ese include
glycine, d-serine, and d-cycloserine. Clinical trials
binding
site
Outside cell
Cell
membrane
Inside cell
Figure a Both glycine and glutamate must occupy their separate binding sites
on the NMDA receptor for the channel to open.
binding
site
Glycine
NMDA receptor
(channel closed)
2+
Ca
and Na
enter cell
NMDA receptor
(channel open)
+
Box 18.2 Dopamine, glutamate, and the biological basis of schizophrenia
IC
(mol/l)
have indicated a therapeutic eect when these are
used as adjunct therapy with established
neuroleptics. On a cautious note, not all studies
have shown a benecial outcome.
2. Administration of glycine uptake inhibitors. Glycine
is removed from the synapse by an active uptake
mechanism, the glycine transporter, which is found
on nerve terminals and astrocytes. is eective
In addition to action at dopamine receptors, the
antipsychotic drugs are antagonists at a variety of other
neurotransmitter receptors, which notably include
muscarinic acetylcholine receptors and
5-hydroxytryptamine (serotonin) receptors. ese
additional actions have a signicant impact on their use in
the clinic and will be considered later. So why is dopamine
–7
10
–8
10
50
–9
10
Pimozide
Triuperidol
removal system results in a subsaturating level of
glycine in the vicinity of NMDA receptors. Inhibition
of this transporter increases the glycine
concentration at these receptors, enhancing
glutamate neurotransmission at the NMDA receptor.
Both these strategies are being actively pursued,
although whether such drugs will ever achieve routine
clinical use remains to be seen.
receptor antagonism assumed to be responsible for the
central antipsychotic eect? ere are a number of pieces of
evidence connecting dopamine activity and
schizophrenia—some are discussed in Box 18.2—but a
salient example is a paper published in 1976 reporting
anity at dopamine D2 receptors and clinical dose for a
wide range of antipsychotic drugs (Figure 18.4). is
Promazine
Chlorpromazine
Clozapine
Thioridazine
Molindone
Moperone
Haloperidol
Droperidol
Fluphenazine
Trazodone
Prochlorperazine
Triuperazine
Thiothixene
Benperidol
–10
10
0.1 110
Spiroperidol
100 1000
Average clinical dose (mg/day)
Figure 18.4 An early study showing correlation between affinity for dopamine D2
receptors (IC50) and average clinical dose for a variety of antipsychotic drugs.
Despite certain caveats, such as the influence of degree of penetration of the blood–brain barrier
on the extent to which clinical dose correlates with concentration in the brain, this is a compelling
illustration of the relationship between antagonism of dopamine D2 receptors and the response
to antipsychotic medication.
Adapted by permission from Macmillan Publishers Ltd: Seeman P, et al. Antipsychotic drug doses and
neuroleptic/dopamine receptors. Nature 1976; 261: 717–19.
466 Chapter 18 Schizophrenia
showed a good correlation between the two, providing
sound support for the notion that the D2 antagonism
exhibited by these drugs contributes to their clinical benet.
18.2.2 Most antipsychotic drugs are
serotonin (5-HT2) antagonists
e idea that serotonin (5-hydroxytryptamine, 5-HT)
could be involved in schizophrenia is based on the fact
that LSD produces hallucinations (see Chapter 21). is
recreational drug is a partial agonist at serotonin
receptors, specically the 5-HT2A subtype. e majority of
antipsychotic drugs, although not all (e.g. sulpiride), are
eective antagonists at 5-HT2 receptors. For some drugs
(e.g. risperidone), 5-HT2 antagonism has been thought of
as central to the antipsychotic eect. For many others
(e.g. clozapine), this antagonism is believed to
contribute, alongside dopamine receptor blockade, to the
therapeutic response. It is also well established that
serotonin antagonism reduces unwanted movement
eects (i.e. extrapyramidal side eects; see Section
18.2.3). However, the limited direct evidence for serotonin
dysfunction in schizophrenia has discouraged the
development of a serotonin hypothesis.
18.2.3 Movement disorder side effects
(extrapyramidal symptoms)
e earliest modern antipsychotic drugs (which were
often called major tranquillizers, or neuroleptics) include
drugs still commonly in use, and are referred to as typical
antipsychotics. ese rst-generation drugs and their
derivatives have a powerful antipsychotic eect, but they
are also associated with a high incidence of movement
disorders (extrapyramidal side eects) which adversely
aects many schizophrenic patients taking them. is
troubling side eect has severely limited the usefulness of
these drugs and in part motivated the search for dierent
drugs, which resulted in the development of the newer
atypical antipsychotics.
Extrapyramidal side eects will be considered here in
three categories.
• Acute dystonic reaction (oculogyric crisis)—
immediate to short-term onset (see Workbook 15).
• Parkinsonian symptoms including many of the broad
features we have seen in Parkinson’s disease, such as
tremor, rigidity, and abnormal posture. Parkinson’s
innervation to the striatum. It is therefore
understandable that a drug which diminishes the
dopaminergic inuence in the striatum by acting as an
antagonist at D2 receptors could lead to Parkinsonian
symptoms. ese eects may occur from the outset of
taking medication.
• Tardive dyskinesias are a distressing and disabling set
of involuntary movements of the tongue, jaw, and lips
which sometimes follow long-term drug use.
e starkest dierence between these movement
disorders for patient welfare is that, while Parkinsonian
symptoms disappear on withdrawal of the drug, tardive
dyskinesias may persist as a permanent disability.
If we recall the treatment of Parkinson’s disease in
Chapter 17 we will note that symptoms can be relieved
not only by increasing the dopaminergic input (-dopa
therapy), but also by diminishing the cholinergic
inuence in the striatum (see Chapter 17, Figure 17.2).
is is important in two respects when trying to
understand drugs and schizophrenia. Firstly, many
antipsychotic drugs act as antagonists at muscarinic
cholinergic receptors as well as at dopamine receptors.
is anticholinergic eect at the striatum may reduce the
tendency to produce movement eects, i.e. all other
things being equal, drugs with strong anticholinergic
eects may have less pronounced extrapyramidal eects.
Secondly, short-term relief from acute dystonias
(movement and posture dysfunction) may be achieved by
using an antagonist at the muscarinic cholinergic
receptor in the striatum, helping restore the cholinergic–
dopaminergic balance. Shaun’s oculogyric crisis was
treated in this way in Workbook 15.
Importantly though, with respect to these unwanted
movement side eects there is considerable variation in
both patients and drugs. Not all patients are equally
susceptible to Parkinsonian symptoms, and even among
the typical antipsychotics the drugs vary in the incidence
of these extrapyramidal eects. Notably, the atypical
antipsychotics have a lowered tendency to generate
movement disorders, generally explained by dierences
in binding to the subtypes of dopamine receptor, and to
the extent of antagonism at other receptors, such as those
for acetylcholine (as indicated above) and serotonin
(Section 18.2.2).
18.2.4 Other side effects
e antimuscarinic eects include dry mouth, blurred
vision, constipation, and disordered control of urination.
Antimuscarinic eects originating in the brain may
18.2 Drugs in clinical use for the treatment of schizophrenia 467
include confusion. e sedative eects, largely as a result
of H1 receptor antagonism, are important—wanted in
agitated patients for short-term maintenance, but largely
unwanted in long-term maintenance—and vary
considerably between dierent drugs. In addition some
patients may experience other side eects, such as
gynaecomastia (i.e. breast enlargement) and related
symptoms (see Section 18.2.1). is results from
dopamine D2 receptor blockade in hypothalamic
pathways, leading to endocrine imbalances such as
increased prolactin secretion.
In rare cases these drugs increase the risk of cardiac
ventricular arrhythmias and in some extremely rare cases
cause sudden cardiac death. is is likely to be due to
eects of these drugs on specic cardiac K+ channels.
18.2.5 Typical antipsychotic drugs
e introduction of the rst modern antipsychotic drugs
into psychiatric practice in the early 1950s had a major
impact, resulting in large reductions in the number of
chronically hospitalized mental patients. e broad
characteristics of typical (or rst-generation)
antipsychotic drugs are eectiveness against positive
symptoms, poor response of negative symptoms (Figure
18.1), and signicant problems with adverse eects, most
notably movement disorders. ese common
characteristics vary between individual drugs and
individual patients.
Pharmacology of typical antipsychotics
positive symptoms of schizophrenia with a dose-related
sedative eect, without concurrent clouding of
consciousness. A number of phenothiazines have been
developed, and these may usefully be classied into three
types according to their risk of sedative, anticholinergic,
and extrapyramidal eects (Table 18.1).
e butyrophenones are a dierent chemical class of
antipsychotics which includes haloperidol and
benperidol. Haloperidol is a widely prescribed drug with
low propensity for sedative and antimuscarinic eects,
but importantly the use of these compounds is restricted
by their high risk of extrapyramidal side eects.
Chlorpromazine and haloperidol are the standard typical
antipsychotics. Other typical antipsychotics which are
neither phenothiazines nor butyrophenones include
pimozide, flupentixol, and zuclopenthixol. ese drugs
tend to have a clinical pharmacology like Group 3
phenothiazines (Table 18.1), namely low sedative and
anticholinergic propensity and high risk of
extrapyramidal eects. is critical tendency of drugs,
which otherwise have a very desirable clinical
pharmacology, to produce movement disorders favours
use of the drugs classed as atypical antipsychotics.
However, before discussing these atypical drugs, it is of
interest to note that sulpiride is a drug that is often
classied as a typical antipsychotic, but has a low risk of
sedative, antimuscarinic, and extrapyramidal side eects.
e receptor pharmacology of four typical antipsychotics
is outlined in Table 18.2.
Phenothiazines are a chemically dened group of drugs.
Included is chlorpromazine (structure shown in Chapter
19, Figure 19.1), the drug which had such a major impact
on psychiatric practice following its introduction in 1952.
Its use made it possible, for the rst time, to reduce the
Table 18.1 Classifying the phenothiazine antipsychotics
Sedative Antimuscarinic Extrapyramidal Examples
Group 1 High Moderate Moderate Chlorpromazine
Group 2 Moderate High Low Pericyazine
Group 3 Moderate Moderate/low High Fluphenazine
18.2.6 Atypical antipsychotics
e newer atypical (or second-generation) antipsychotic
drugs are a very mixed group in terms of their
pharmacology and clinical eects.
Levomepromazine
Promazine
Pipotiazine
Prochlorperazine
Perphenazine
Trifluoperazine
468 Chapter 18 Schizophrenia
Table 18.2 Some typical antipsychotics and their afnity
for neurotransmitter receptors
Drug Antagonist at receptors (affinity)
D1D
Chlorpromazine + + + + + + + + + + +
Haloperidol + + + + – + –
Flupentixol + + + + + – + + + + +
Sulpiride – + + + – – –
The number of + signs indicates the relative affinity of the drug for the
receptor.
mACh 5-HT2Histamine H
2
Pharmacology of atypical antipsychotics
In common with the older drugs, these antipsychotics are
antagonists at dopamine receptors, but dier in their
selectivity for the dierent receptor subtypes. ey may
also dier from typical antipsychotics in the strength with
which they bind to dopamine receptors (anity). Both
these characteristics can be used to explain why atypical
antipsychotics may have less eect on dopamine in the
striatum, while eectively inhibiting dopamine in the
corticolimbic areas.
• Atypical antipsychotics are competitive antagonists at
dopamine receptors. A drug with lower anity may be
ineective at the dopamine receptors in the striatum,
where the synaptic dopamine concentration is very
high, but eective when in competition with the much
lower dopamine levels at the receptors within the
corticolimbic areas.
• e dierential distribution of D3 and D4 receptors, with
a much greater prevalence in corticolimbic
areas (Box 18.1), may mean that a drug selective for
these receptor subtypes exhibits selectivity for these
brain areas.
• Both typical and atypical antipsychotic drugs are ‘dirty’
drugs, acting as antagonists at receptors for a variety of
neurotransmitters. It is likely that the combination of
antagonist eects of some atypical drugs helps some
patients. In particular, antagonism at the serotonin
5-HT2A receptor may improve the clinical outcome with
some atypical drugs.
Major atypical antipsychotic drugs include amisulpride
(a longer-acting derivative of sulpiride), aripiprazole,
olanzapine, quetiapine, risperidone, and clozapine.
Risperidone, clozapine, and olanzapine are notable for
their high ratio of blocking 5-HT2A to dopamine receptors.
Generally these drugs have the characteristics indicated
above for atypical antipsychotics: increased eectiveness
(compared with typical antipsychotics) against negative
symptoms, with a reduced propensity for extrapyramidal
1
movement side eects. Clozapine is important as a very
eective antipsychotic agent, targeting D4 receptors with
a degree of selectivity. However, it must be used with
caution since it has a propensity to cause the dangerous
condition of agranulocytosis (lowered white blood cells,
namely neutrophils) necessitating regular (e.g. weekly)
monitoring of blood counts. For this reason clozapine use
is restricted to certain categories of patients who have
failed to respond to at least two other antipsychotics.
ere are other situations when atypical drugs carry
certain additional risks in some patients, for instance a
recognized increased risk of stroke in elderly patients
with dementia indicates that olanzapine and risperidone
should not be used (see also the discussion of Alzheimer’s
dementia in Chapter 17).
e receptor pharmacology of some atypical
antipsychotics is outlined in Table 18.3.
Aripiprazole is an interesting drug in that its partial
agonist action at D2 receptors (see Chapter 2), combined
with its high anity, means that in the striatum it will
reduce the eect of endogenous dopamine, but provide a
weak stimulation of its own. It will therefore provide a
degree of D2 stimulation in the striatum, perhaps
explaining the low tendency to give movement eects.
e therapeutic benet is likely to come from reduced D2
stimulation elsewhere in the brain combined with
reduced 5-HT receptor inuence.
18.2.7 Strategy in the drug treatment of
schizophrenia
It should be noted that there is considerable dispute as to
the relative merits of atypical and typical antipsychotics.
Combined with the wide variation in individual patient
response, both of clinical benet and unwanted eects,
this means that a single strategy for drug treatment of
schizophrenia which is consistent over time and across
dierent countries is unlikely to be found. In Workbook
15 Shaun is started on a typical neuroleptic (haloperidol)
and only commences an atypical drug when this is not
eective. e rst atypical drug he used was olanzapine,
but he eventually settled with clozapine as the most
eective for him. His story illustrates some persistent
themes.
18.2 Drugs in clinical use for the treatment of schizophrenia 469
Table 18.3 Atypical antipsychotics and their afnity for neurotransmitter receptors
Drug Antagonist at receptors (affinity)
D
1
Risperidone – + + + + + + + + + + + +
Olanzapine + + + + + + + + + +
Clozapine
Aripiprazole
The number of + signs indicates the relative affinity of the drug for the receptor.
a
Clozapine may have some agonist activity at 5-HT1A receptors, D1 dopamine receptors, and M4 muscarinic
cholinergic receptors in some brain areas.
b
Aripiprazole is a partial agonist at dopamine D2 and 5-HT1A receptors and an antagonist at 5-HT2A
receptors.
a
+ + + + + + + + + + + + + +
b
– + + + + – + + +
D
2
D
4
mACh 5-HT
2
Histamine H
1
• It is likely that a patient may have to try several drugs
sequentially before the best solution for that individual
is found.
• Only one antipsychotic drug is taken at any one time.
• Anxiolytics in the form of benzodiazepines may be used
in combination with antipsychotic drugs to quieten
agitated patients, reducing the need for sedative doses
of antipsychotic drugs in acute phases of treatment.
• Clozapine, an eective drug with signicant side eects
(i.e. agranulocytosis) is, according to some guidelines,
restricted to patients who have tried two other
antipsychotic drugs, one of which should be an atypical
drug, without satisfactory outcome.
It should also be noted, however, that the treatment of
Shaun in Workbook 15 does not follow a further
recommendation, found in some guidelines, that a newly
diagnosed patient should be prescribed atypical
antipsychotic drugs as rst-line treatment. Shaun’s
treatment illustrates the point that therapy must be
individually tailored, and will vary considerably from one
patient (and one psychiatric practice) to the next.
Here we are concerned with drug treatment, but as in
many other clinical elds it must be remembered that
non-drug aspects of therapy are of crucial signicance—
this is the case for our imaginary patient Shaun where the
initial plan is for medication combined with deescalation (see Workbook 15).
18.2.8 The future for antipsychotic drug
therapy
It is likely that antagonists for the D2 family of dopamine
receptors, in one form or another, will remain the
cornerstone of antipsychotic drug therapy. Here we
mention two avenues of research which may well lead to
changes in the range of drugs available.
• Further development of drugs which target specic
combinations of dopamine receptor subtypes
combined with action at other (mainly biogenic amine)
neurotransmitter receptors. It is becoming increasingly
clear that specic agonist activities, as well as D2 family
antagonism, may lead to an improved therapeutic
response.
• Development of drugs enhancing activity at the
glycine site of the NMDA receptor to upregulate this
aspect of glutamate neurotransmission (Box 18.2).
Evidence suggests that such drugs may serve as
adjuncts to dopamine antagonists, rather than
replacing them.
More dopamine antagonists (and agonists)?
e developments outlined below all have dopamine
receptor antagonism central to the putative antipsychotic
eect, in some cases with additional eects at other
neurotransmitter receptors.
• D3 dopamine receptor antagonists Development in
this area may potentially yield drugs eective against
negative symptoms and relatively free from movement
disorders (see Section 18.2.1).
• D2 antagonist/D1 agonist e drug stepholidine has
been isolated from the Chinese herb Stephania
intermedia. It is a combined D1 agonist and D2
antagonist, shown to be active in the prefrontal cortex,
nucleus accumbens, and ventral tegmental area. As D2
receptor hyperactivity and D1 receptor underactivity are
central to the dopamine hypothesis of the development
of schizophrenia (see Box 18.2), this drug is of obvious
interest as a therapeutic agent.
470 Chapter 18 Schizophrenia
• Asenapine is a new drug for the treatment of manic–
psychotic episodes associated with bipolar illness
(Chapter 19). It has also shown some positive eects on
the acute symptoms of schizophrenia. It displays D2
antagonism, but more potent antagonism for D3 and a
variety of 5-HT receptors.
One of the themes that candidate antipsychotic drugs
such as stepholidine and asenapine illustrate is that a
clean drug, acting at only one receptor, will probably not
give the greatest benecial eect. What is required is a
drug targeting multiple specied receptors, but lacking
eect at others which are associated with unwanted
eects. Obviously this is demanding of drug design, and is
made more dicult by the gaps in our understanding of
the underlying causes of schizophrenia. To complicate
matters still further, it is likely that individual patients will
respond dierently to drugs acting at multiple targets, so
that individualized therapy will be required.
More glutamate and less dopamine?
A central theme of antipsychotic drugs is their
antagonism at the dopamine receptors in the brain.
Recently, however, a new approach apparently
independent of dopamine antagonism has evolved which
may possibly result in entirely novel drugs. A close
relative of the anaesthetic ketamine, phencyclidine
(PCP), is a drug of abuse that produces a very faithful
psychosis-like episode in some individuals. Both positive
and negative symptoms are mimicked. PCP is an
antagonist at NMDA receptors for the excitatory
neurotransmitter glutamate (see Box 18.2 and Chapter
16). is has led to the hypothesis that a reduction of
glutamate activity in the brain may contribute to the
neuropathology of schizophrenia, and that drugs that
increase activity at NMDA receptors may therefore help
resolve symptoms. However, glutamate or similar
agonists acting at all glutamate receptors are cytotoxic,
and so cannot be used.
Glycine acts as a co-agonist at the NMDA receptor. is
means that glycine and glutamate binding to their
respective sites is necessary for receptor activation (see
Box 18.2, Figure a). is has led to some interesting drug
development strategies, in particular the use of glycine
agonists and the development of inhibitors of glycine
uptake as potential antipsychotic drugs. ese ideas are
developed a little further in Box 18.2; the approach shows
how the attention of pharmacologists may oer
fundamentally novel help for those suering from this
devastating disorder. On a cautious note, however, it is
likely that if NMDA-enhancing antipsychotic drugs do
become available, they will act as adjunct therapy to the
D2 antagonist medications, perhaps targeting negative
symptoms, rather than being used as stand-alone
therapy.
Key references and suggested reading
Conn PJ, Lindsley CW, Jones CK. Activation of metabotropic
glutamate receptors as a novel approach for the treatment of
schizophrenia. Trends Pharmacol Sci 2009; 30(1): 25–31.
Laruelle M, Frankle WG, Narendran R, Kegeles LS, Abi-
Dargham A. Mechanism of action of antipsychotic drugs:
from dopamine D2 receptor antagonism to glutamate NMDA
facilitation. Clin erapeut 2005; 27(Suppl A): S16–24.
Lechner S. Glutamate-based therapeutic approaches:
inhibitors of glycine transport. Curr Opin Pharmacol 2006; 6:
75–81.
Livingston M. Choosing an antipsychotic: an evidence-based
approach. Prescriber 2009; 20(7): 7–9.
SUMMARY OF COMMON DRUGS USED FOR SCHIZOPHRENIA
18.2 Drugs in clinical use for the treatment of schizophrenia 471
Therapeutic
group
Typical or firstgeneration
antipsychotics
Class/drugs Mechanism of action Common clinical uses Comments Common adverse drug
reactions
Phenothiazines
Group 1:
Chlorpromazine
Levomepromazine
Promazine
Group 2:
Pericyazine
Pipotiazine
Group 3
Fluphenazine
Prochlorperazine
Perphenazine
Antagonist at D1 and D
receptors
Psychosis
2
Schizophrenia
Anxiety
Intractable hiccups
Nausea
High sedative, moderate
antimuscarinic and
extrapyramidal side effects
Moderate sedative, high
antimuscarinic, and low
extrapyramidal side effects
Moderate sedative,
moderate/low
antimuscarinic, and high
extrapyramidal side effects
See comments
Extrapyramidal side effects:
Dystonia
Akathisia
Parkinsonian symptoms
Tardive dyskinesia
Neuroleptic malignant
syndrome
Antimuscarinic side effects:
Dry mouth
Urinary retention
Sedative effects
Trifluoperazine
Butyrophenones
Benperidol
Haloperidol
Antagonist at D1 and D2
dopamine receptors
Haloperidol
Psychosis
Schizophrenia
Low antimuscarinic and
high extrapyramidal effects
Anxiety
Tourette’s syndrome
Hiccups
Benperidol
Control of deviant
antisocial sexual behaviour
Diphenylbutylpiperidines
Pimozide
1) Antagonist at D2 receptor
2) Blocks voltage-operated
calcium channels
3) Thought to be antagonist
Schizophrenia
Tourette’s syndrome
Low sedative and
anticholinergic
propensity and high risk of
extrapyramidal effect
at opiate receptors
Thioxanthenes
Flupentixol
Antagonist at D1 and D2
dopamine receptors
Psychosis
Schizophrenia
Zuclopenthixol
Substituted benzamides
Sulpiride
Amisulpride (derivative of sulpiride,
Antagonist at D2 dopamine
receptors
Low risk of sedative,
antimuscarinic, and
extrapyramidal effects
atypical antipsychotic drug but
sharing characteristics with sulpiride)